Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of <scp>J</scp>apanese patients with novel <scp><i>SCARB2</i></scp> mutations

Fu, Yuping; Aida, Izumi; Tada, Masayoshi; Tada, Mari; Toyoshima, Yasuko; Takeda, Shingo; Nakajima, Takashi; Naito, Haruhiko; Nishizawa, Masatoyo; Onodera, Osamu; Kakita, Akiyoshi; Takahashi, Hitoshi

doi:10.1111/nan.12057

Cited by 16 publications

(22 citation statements)

References 18 publications

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“…Widespread deposition of abnormal, extraneuronal brown pigment in the brain, with no neuronal loss or significant gliosis, has been reported in AMRF patients (Andermann et al, 1986;Badhwar et al, 2004), and more recently in two patients with PME without renal failure associated with SCARB2 mutations (Fu et al, 2014). Based on the staining characteristics, it has been suggested that the pigment consists of lipofuscin-like oxidized lipid or proteolipid (Badhwar et al, 2004).…”

Section: Histologymentioning

confidence: 98%

“…Since this initial report, other cases have been reported and the clinical features of PME without renal failure associated with SCARB2 have been described (Rubboli et al ., ; Guerrero‐López et al ., ; Higashiyama et al ., ; Fu et al ., ; Zeigler et al ., ). Features seen in these patients included a variable severity of epilepsy: from uncontrolled seizures or status epilepticus with prominent photosensitivity in patients with adolescent onset, to infrequent or no major seizures in patients with a more delayed onset (Rubboli et al ., ), late onset in adulthood (Higashiyama et al ., ; Fu et al ., ), and the occurrence of dementia (Fu et al ., ). These findings suggest that SCARB2 mutations in patients with PME without renal complications might not be rare and that SCARB2 gene mutations should therefore be evaluated even in the absence of renal involvement.…”

Section: Clinical Features Of Action Myoclonus Renal Failurementioning

confidence: 98%

“…Interestingly, the patients without renal failure reported by Fu et al . () also showed neurodegenerative changes, such as neuronal loss and gliosis in the brain, including the pallidoluysian and cerebello‐olivary systems and the spinal cord. The authors speculate that the neuronal loss and gliosis in the pallidoluysian and cerebello‐olivary systems may be responsible for the patients’ involuntary movements and cerebellar dysfunction.…”

Section: Histologymentioning

confidence: 99%

“…Based on the staining characteristics, it has been suggested that the pigment consists of lipofuscin-like oxidized lipid or proteolipid (Badhwar et al, 2004). The deposits of pigment granules are extraneuronal, in astrocytes or in the extracellular space, especially in the cerebellar and cerebral cortices without any increase in intraneuronal lipofuscin (Badhwar et al, 2004;Fu et al, 2014). Interestingly, the patients without renal failure reported by Fu et al (2014) also showed neurodegenerative changes, such as neuronal loss and gliosis in the brain, including the pallidoluysian and cerebello-olivary systems and the spinal cord.…”

Section: Histologymentioning

confidence: 99%

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SCARB2/LIMP2 deficiency in action myoclonus‐renal failure syndrome

Dibbens¹,

Schwake²,

Säftig³

et al. 2016

Epileptic Disorders

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Action myoclonus–renal failure syndrome (AMRF) is an autosomal recessive progressive myoclonus epilepsy (PME) associated with renal dysfunction that appears in the second or third decade of life and that is caused by loss‐of‐function mutations in the SCARB2 gene encoding lysosomal integral membrane protein type 2 (LIMP2). Recent reports have documented cases with PME associated with SCARB2 mutations without renal compromise. Additional neurological features can be demyelinating peripheral neuropathy, hearing loss and dementia. The course of the disease in relentlessly progressive. In this paper we provide an updated overview of the clinical and genetic features of SCARB2‐related PME and on the functions of the LIMP2 protein.

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Section: Histologymentioning

confidence: 98%

Section: Clinical Features Of Action Myoclonus Renal Failurementioning

confidence: 98%

Section: Histologymentioning

confidence: 99%

Section: Histologymentioning

confidence: 99%

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SCARB2/LIMP2 deficiency in action myoclonus‐renal failure syndrome

Dibbens¹,

Schwake²,

Säftig³

et al. 2016

Epileptic Disorders

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“…LIMP-2-deficient (LIMP-2 −/− ) mice (4) are a valid disease model for AMRF. To date, several SCARB2 mutations have been identified in AMRF, as well as in some PME cases (5,6). AMRF/PME mutants mislocalize to the endoplasmic reticulum (ER) and fail to transport GC to lysosomes (7,8).…”

mentioning

confidence: 99%

LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance

Rothaug¹,

Zunke²,

Mazzulli

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

105

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Significance Our report highlights, for the first time to our knowledge, a distinct relationship between lysosomal integral membrane protein type-2 (LIMP-2) expression, β-glucocerebrosidase (GC) activity, and clearance of α-synuclein. In LIMP-2–deficient mice, increased levels of endogenous α-synuclein led to severe neurological deficits and premature death. We found that loss of LIMP-2 reduced lysosomal GC activity, resulting in lipid storage, disturbed autophagic/lysosomal function, and α-synuclein accumulation leading to neurotoxicity of dopaminergic neurons as well as apoptotic cell death and inflammation. Furthermore, heterologous overexpression of functional LIMP-2 enhanced α-synuclein clearance and improved lysosomal activity of GC. Our results suggest that lysosomal GC activity can be influenced via its interaction with LIMP-2, which could be a promising strategy for the treatment of synucleinopathies.

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Movement Disorders and Renal Diseases

Bhowmick

Lang

2020

Movement Disord Clin Pract

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Movement disorders often emerge from the interplay of complex pathophysiological processes involving the kidneys and the nervous system. Tremor, myoclonus, ataxia, chorea, and parkinsonism can occur in the context of renal dysfunction (azotemia and electrolyte abnormalities) or they can be part of complications of its management (dialysis and renal transplantation). On the other hand, myoglobinuria from rhabdomyolysis in status dystonicus and certain drugs used in the management of movement disorders can cause nephrotoxicity. Distinct from these well-recognized associations, it is important to appreciate that there are several inherited and acquired disorders in which movement abnormalities do not occur as a consequence of renal dysfunction or vice versa but are manifestations of common pathophysiological processes affecting the nervous system and the kidneys. These disorders are the emphasis of this review. Increasing awareness of these conditions among neurologists may help them to identify renal involvement earlier, take timely intervention by anticipating complications and focus on therapies targeting common mechanisms in addition to symptomatic management of movement disorders. Recognition of renal impairment in a patient with complex neurological presentation may narrow down the differentials and aid in reaching a definite diagnosis.

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Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations

Cited by 16 publications

References 18 publications

SCARB2/LIMP2 deficiency in action myoclonus‐renal failure syndrome

SCARB2/LIMP2 deficiency in action myoclonus‐renal failure syndrome

LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance

Movement Disorders and Renal Diseases

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